Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules (i.e., ions, water, nutrients), large molecules (i.e., albumin, antibodies, cytokines, nucleic acids, lipids) or even whole cells (i.e., lymphocytes on their way to a site of inflammation) in and out of the blood vessel. A single layer of endothelial cells, called endothelium, line the blood vessel walls and the heart chambers. Gaps which are located between the endothelial cells (called cell junctions) are able to open or close, but are strictly regulated depending on the type and physiological state of the tissue.
There are many triggers for vascular permeability. For example, an increase in vascular permeability occurs at the very beginning of the inflammatory response and is initially triggered by agents released by mast cells, which activate endothelial cell receptors promoting endothelial cell retraction and gap junction disorganization, leading to gap formation between the endothelial cells in venules and capillaries. (Garcia Leme, J., Hamamura, L., Leite, M. P., Rocha e Silva, M., 1973. Pharmacological analysis of the acute inflammatory process induced in the rat's paw by local injection of carrageenan and by heating. Br. J. Pharmacol. 48, 88-96.; Holsapple, M. P., Schnur, M., Yim, G. K., 1980. Pharmacological modulation of edema mediated by prostaglandin, serotonin and histamine. Agents Actions 10, 368-373.) The subsequent leakage of macromolecules to the injured tissue is the main cause of edema formation. A neutrophil-endothelium interaction, which is necessary for neutrophil migration, will then contribute to a more persistent increase in vascular permeability (Kubes, P., Gaboury, J. P., 1996. Rapid mast cell activation causes leukocyte-dependent and -independent permeability alterations. Am. J. Physiol. 271, H2438-H2446.; Lewis, R. E., Granger, H. J., 1986. Neutrophil-dependent mediation of microvascular permeability. Fed. Proc. 45, 109-113).
In acute inflammation, fluid loss from blood vessels with increased permeability occurs in distinct phases: (1) an immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine and leukotrienes on endothelium; (2) a delayed response starting at about 2 hours and lasting for about 8 hours, mediated by kinins, complement products, and other factors; and (3) a prolonged response that is most noticeable after direct endothelial injury, for example, after burns.
A critical function of inflammation is to deliver leukocytes to the site of injury and to activate the leukocytes to perform their normal functions in host defense. Leukocytes ingest offending agents, kill bacteria and other microbes, and get rid of necrotic tissue and foreign substances. However, untoward events manifest themselves as a result of the defensive potency of leukocytes. For example, leukocytes may induce tissue damage and prolong inflammation and leukocyte products that destroy microbes and necrotic tissues can also injure normal host tissues.
Increased vascular permeability is also exhibited by certain viral diseases called viral hemorrhagic fevers (VHFs). VHF refers to a group of illnesses that are caused by several distinct families of viruses. In general, the term “viral hemorrhagic fever” is used to describe a severe multisystem syndrome in which the overall vascular system is damaged, and the body's ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage; however, the bleeding itself is rarely life-threatening. While some types of VHFs can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. Examples include Ebola, Marburg, Lassa fever, and yellow fever viruses, among others.
Currently, there is no universal, satisfactory treatment for many of the VHFs, particularly those that cause life-threatening disease. Treatments include transfusion of serum from patients that have recovered from the viral infection as well as aggressive treatment of symptoms including nausea, vomiting, diarrhea, fever, and bleeding.
It is believed that a treatment option that could reduce abnormal vascular permeability associated with certain diseases and conditions or which is a symptom of certain diseases and conditions would vastly benefit patients who otherwise have few treatment options. In particular, a treatment option that could decrease vascular permeability could prove very useful in the management of the notoriously difficult VHF diseases.
Accordingly, it is an object of the instant invention to provide such a treatment options.